rs144426436

chr20-36198016-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_012156.2(EPB41L1):c.1643A>G(p.Lys548Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,613,530 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (24 hom.)
• Consequence: EPB41L1 NM_012156.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.65

Genes affected

EPB41L1 (HGNC:3378): (erythrocyte membrane protein band 4.1 like 1) Erythrocyte membrane protein band 4.1 (EPB41) is a multifunctional protein that mediates interactions between the erythrocyte cytoskeleton and the overlying plasma membrane. The encoded protein binds and stabilizes D2 and D3 dopamine receptors at the neuronal plasma membrane. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EPB41L1
• BP4: Computational evidence support a benign effect (MetaRNN=0.010875225).
• BP6: Variant 20-36198016-A-G is Benign according to our data. Variant chr20-36198016-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 210945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 413 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB41L1	NM_012156.2	c.1643A>G	p.Lys548Arg	missense_variant	14/22	ENST00000338074.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB41L1	ENST00000338074.7	c.1643A>G	p.Lys548Arg	missense_variant	14/22	1	NM_012156.2	P5

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 413 AN: 152054 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00707

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00284 AC: 707 AN: 248540 Hom.: 3 AF XY: 0.00280 AC XY: 378 AN XY: 134976

Gnomad AFR exome AF: 0.000633

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000898

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00921

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00386 AC: 5643 AN: 1461356 Hom.: 24 Cov.: 37 AF XY: 0.00375 AC XY: 2724 AN XY: 726986

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.00435

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152174 Hom.: 1 Cov.: 32 AF XY: 0.00276 AC XY: 205 AN XY: 74408

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00707

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00341 Hom.: 1

Bravo AF: 0.00226

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00263 AC: 319

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	EPB41L1: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 20, 2015

- -

EPB41L1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.91	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.58	N;N;N;.;.;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.43	T;T;T;.;.;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T;T;T;T
Polyphen		0.57	P;P;P;.;P;P;.;.
Vest4		0.27
MVP		0.83
MPC		0.31
ClinPred		0.015	T
GERP RS		4.0
Varity_R		0.056
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144426436; hg19: chr20-34785938; COSMIC: COSV99058415;